The magnitude and the duration of cytokine action are essential in determining the response to foreign antigens and allergens. Thus, the action of cytokines is tightly regulated both developmentally and within the cell. The Suppressor of Cytokine Signaling (SOCS) protein family represents a novel group of cytoplasmic negative feedback regulators of type I and II cytokines. SOCS-1 is a critical regulator of multiple signaling pathways, including those activated by cytokines that regulate immunoglobulin heavy chain class switching to IgE. SOCS-1 can inhibit the action of IFN-3, which decreases IgE production, and IL-4, which promotes IgE production. Therefore, how differences in SOCS-1 levels would affect IgE levels and atopic immune responses was unclear. Analysis of mice with mutations in the SOCS-1 gene demonstrates that with loss of SOCS-1 alleles the levels of IgE increase. This suggests that SOCS-1 is an inhibitor of IgE in vivo. A genetic association study was performed in 474 asthmatics to determine if genetic variation in the SOCS-1 locus correlates with altered levels of IgE. Carriers of a novel, single nucleotide polymorphism (SNP) in the SOCS-1 gene were found to have significantly lower levels of serum IgE as compared with homozygotes for the allele. Analysis demonstrated that this SNP was in linkage disequilibrium with a SNP at position -820 of the SOCS-1 promoter. The promoter SNP increases transcriptional activity of the SOCS-1 promoter. Consistent with this observation, the presence of this polymorphism within the promoter sequence abolished binding of Yin-Yang-1, which is identified as a negative regulator of SOCS-1 transcriptional activity. These data suggest that genetic variation in the promoter of this key regulator of cytokine signaling may affect IgE production. We propose to extend these data to determine how polymorphisms of the SOCS-1 locus affect SOCS-1 gene expression and the mechanism by which variable levels of SOCS-1 alter IgE levels in both mice and humans. PUBLIC HEALTH RELEVANCE Genetic data in mice and humans suggest that SOCS-1 is an inhibitor of IgE levels. This application proposes a series of experiments to determine the mechanisms by which SOCS-1 inhibits IgE and how genetic variants in the human SOCS-1 locus affect IgE levels.